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MolecularMD Pulls PMA After FDA Says Companion Dx Not Needed to Establish Ponatinib Efficacy, Safety

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MolecularMD, a diagnostics firm that was developing a companion test to personalize treatment with Ariad Pharmaceuticals' leukemia drug ponatinib, announced this week that it has voluntarily withdrawn its premarket approval application for the test.

In a joint statement, Ariad and MolecularMD said that the companies were recently informed by the US Food and Drug Administration's Center for Devices and Radiological Health that MolecularMD's BCR-ABL T315I Mutation Test is "no longer considered to be a companion diagnostic test for ponatinib."

After receiving this notification from the agency, MolecularMD withdrew its PMA submission. "The FDA determined that knowing the T315I mutation status of a patient was not essential to safe and effective therapy with ponatinib," a company spokesperson told PGx Reporter sister publication GenomeWeb Daily News.

Meanwhile, Ariad's rolling new drug application for ponatinib, which the company initiated earlier this year, is still under review at the FDA without a companion test. Ariad is seeking approval for ponatinib as a treatment for resistant or intolerant chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Data from the pivotal Phase II trial PACE, which Ariad submitted as part of its NDA for ponatinib, suggest that the drug is sufficiently effective across the broader population of CML and Ph-positive ALL who have become resistant to other tyrosine kinase inhibitors, and as such, doesn't require a companion test.

According to publicly available statements from Ariad, the company designed the drug to bind to the BCR-ABL tyrosine kinase and inhibit the "entire spectrum of mutants conferring resistance against other TKIs, including the T315I" mutation, which makes patients resistant to all current therapies for these diseases. Ariad estimates that between 15 percent and 30 percent of resistance-causing BCR-ABL mutations are T315I mutations.

"The drug is effective in all settings: with no mutations, with T315I, or with other mutations, making the companion test less impactful," Jorge Cortes of University of Texas's MD Anderson Cancer Center, who led the PACE study, told PGx Reporter.

PACE

In PACE, 444 treated patients were divided into several disease cohorts – chronic-phase, accelerated-phase, or blast-phase CML or Ph-positive ALL – and treated with ponatinib. Patients' responses were also analyzed based on whether they were carriers of the T315I mutation, which previous studies have shown to confer resistance. In the trial, researchers determined patients' T315I status with MolecularMD's Sanger sequencing-based companion test.

Ariad submitted data to the FDA on patients' responses to ponatinib after they were treated for at least six months. In PACE, 93 percent of patients had been treated previously with at least two tyrosine kinase inhibitors.

Of 267 chronic-phase CML patients, 54 percent achieved a major cytogenetic response and 44 percent achieved a complete cytogenetic response. There were 64 evaluable T315I carriers with chronic-phase CML in PACE, and 70 percent, or 45 patients, achieved a major cytogenetic response and 66 percent saw a complete cytogenetic response. Meanwhile, in chronic-phase CML patients without the T315I mutation, 99 out of 203 evaluable patients, or 49 percent, saw a major cytogenetic response.

In the advanced-phase CML cohort, involving 177 patients, Ariad reported that 39 out of 65 study participants with an accelerated form of the disease, or 60 percent, saw a major hematologic response. In this subset there were 18 patients positive for the T315I mutation, and half achieved a major hematologic response.

Seventeen out of 48 patients with blast-phase CML or Ph-positive ALL who were resistant or intolerant to prior TK inhibitors achieved a major hematologic response. In this group, 46 patients had a T315I mutation, of which 33 percent had a major hematologic response.

Meanwhile, 34 percent of accelerated phase CML patients and 27 percent of those with blast-phase or Ph-positive ALL had a major cytogenetic response. In these same subsets, 20 percent of accelerate phase and 23 percent of blast-phase and Ph-positive ALL achieved a complete cytogenetic response.

In PACE, patients treated with ponatinib commonly experienced thrombocytopenia, rash, dry skin, stomach pain, and headaches.

Continuing Companion Dx Collaboration

According to Cortes, breaking out the PACE cohort into T315I mutation carriers and non-carriers was a learning experience about the underlying disease biology, but the data show that a companion test is not necessary for the drug. Mutation testing with a companion test "would be more relevant for dasatinib [Bristol-Myers Squibb's Sprycel], nilotinib [Novartis's Tasigna], or bosutinib [Pfizer's Bosulif] than for ponatinib," he noted, "because they do not work if there is [a] T315I [mutation]."

Earlier this month, the FDA approved Bosulif as a treatment for chronic, accelerated, or blast phase Ph-positive CML for patients who are resistant or intolerant to other TK inhibitors, such as Novartis' Gleevec (PGx Reporter 9/5/2012). The drug wasn't approved with a companion test, but there is data suggesting that patients with certain BCR-ABL mutations may not respond to the drug.

For example, a study conducted by researchers from Wyeth and the University of Milano-Bicocca tested the activity of Bosulif, Sprycel, Gleevec, and Tasigna against a panel of 18 BCR-ABL mutations associated with Gleevec resistance in CML and Ph-positive ALL. The researchers, led by Sara Redaelli of the University of Milano-Bicocca, identified eight mutations conferring moderate resistance to Bosulif, 10 mutations conferring moderate resistance to Sprycel, and 13 mutations showing moderate resistance to Tasigna and Gleevec. In addition to T315I, the V299L mutation showed high resistance for Bosulif and E255V for Gleevec and Tasigna. T315I represented the only highly resistant mutation for Sprycel.

"We believe that ponatinib works in patients with any mutation, so mutation testing (companion diagnostic) is not necessary," an Ariad spokesperson said via email. "Other drugs (bosutinib, for example) work in some, but not all mutations. For those drugs, a companion diagnostic that detects a patient’s mutation would be helpful to the physician."

Despite withdrawing its PMA for ponatinib, MolecularMD continues to provide diagnostic testing services for Ariad's drug trials. The companies have not disclosed which drug programs they are collaborating on, but the Ariad spokesperson confirmed that the company will not pursue a companion diagnostic strategy for any of the indications for which ponatinib is being investigated.

In PACE, 30 percent of chronic-phase CML patients and 50 percent of 64 patients with the T315I mutation saw a major molecular response. This provided positive signs for another Phase III trial that Ariad is conducting comparing ponatinib against Gleevec as a first-line treatment for newly-diagnosed CML patients. Gleevec is slated to go off patent in 2015. Other front-line CML treatments currently available on the market include Sprycel and Tasigna.

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